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Stefan Riedl, Friedrich-Wilhelm Röhl, Walter Bonfig, Jürgen Brämswig, Annette Richter-Unruh, Susanne Fricke-Otto, Markus Bettendorf, Felix Riepe, Gernot Kriegshäuser, Eckhard Schönau, Gertrud Even, Berthold Hauffa, Helmuth-Günther Dörr, Reinhard W Holl, Klaus Mohnike, and the AQUAPE CAH Study Group

Congenital adrenal hyperplasia (CAH) due to CYP21A2 gene mutations is associated with a variety of clinical phenotypes (salt wasting, SW; simple virilizing, SV; nonclassical, NC) depending on residual 21-hydroxylase activity. Phenotypes and genotypes correlate well in 80–90% of cases. We set out to test the predictive value of CAH phenotype assignment based on genotype classification in a large multicenter cohort. A retrospective evaluation of genetic data from 538 CAH patients (195 screened) collected from 28 tertiary centers as part of a German quality control program was performed. Genotypes were classified according to residual 21-hydroxylase activity (null, A, B, C) and assigned clinical phenotypes correlated with predicted phenotypes, including analysis of Prader stages. Ultimately, concordance of genotypes with clinical phenotypes was compared in patients diagnosed before or after the introduction of nationwide CAH-newborn screening. Severe genotypes (null and A) correlated well with the expected phenotype (SW in 97 and 91%, respectively), whereas less severe genotypes (B and C) correlated poorly (SV in 45% and NC in 57%, respectively). This was underlined by a high degree of virilization in girls with C genotypes (Prader stage >1 in 28%). SW was diagnosed in 90% of screening-positive babies with classical CAH compared with 74% of prescreening patients. In our CAH series, assigned phenotypes were more severe than expected in milder genotypes and in screened vs prescreening patients. Diagnostic discrimination between phenotypes based on genotypes may prove overcome due to the overlap in their clinical presentations.

Open access

Heike Hoyer-Kuhn, Angela Huebner, Annette Richter-Unruh, Markus Bettendorf, Tilman Rohrer, Klaus Kapelari, Stefan Riedl, Klaus Mohnike, Helmuth-Günther Dörr, Friedrich-Wilhelm Roehl, Katharina Fink, Reinhard W Holl, and Joachim Woelfle

Objective: Treatment in classic congenital adrenal hyperplasia (CAH) is necessary to compensate for glucocorticoid/mineralocorticoid deficiencies and to suppress androgen excess. Hydrocortisone (HC) is preferred in growing children with classic CAH, but recommendations regarding dosage/administration are inconsistent. Aim of the study was to evaluate HC dosing in children with CAH in relation to chronological age, sex, and phenotype based on a multicentre CAH registry.

Design: The CAH registry was initiated in 1997 by the AQUAPE in Germany. On December 31st 2018, data from 1571 patients were included.

Methods: A custom-made electronic health record software is used at the participating centres. Pseudonymized data are transferred for central analysis. Parameters were selected based on current guidelines. Descriptive analyses and linear regression models were implemented with SAS 9.4.

Results: We identified 1288 patients on exclusive treatment with hydrocortisone three times daily (604 boys; median age 7.2 years; 817 salt-wasting phenotype, 471 simple-virilizing phenotype). The mean [lower-upper quartiles] daily HC dose [mg/m² body surface area] was 19.4 [18.9-19.8] for patients <3 months (n=329), 15.0 [14.6-15.3] age ≥3-12 months (n=463), 14.0 [13.7-14.3] age 1-5.9 years (n=745), 14.2 [14.0-14.5] age 6 years-puberty entry (n=669), and 14.9 [14.6-15.2] during puberty-18 years (n=801). Fludrocortisone was administered in 74.1% of patients (median daily dosage 88.8 µg).

Conclusion: Our analyses demonstrated still a high proportion of children with HC doses higher than recommended. This evaluation provides comprehensive information on nationwide hydrocortisone substitution dosages in children with CAH underlining the benefit of systematic data within a registry to assess daily practice.